rs58371799

Variant names:

• chrX-48684427-AC-A
• rs58371799
• NM_000377.3:c.273+11delC

Your query was ambiguous. Multiple possible variants found:

• chrX-48684427-AC-A
• chrX-48684427-AC-ACC
• chrX-48684427-AC-ACCC
• chrX-48684427-AC-ACCCC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The ENST00000376701.5(WAS):​c.273+5delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000368 in 1,085,985 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: WAS ENST00000376701.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0540
• Publications: 3 publications found

Genes affected

WAS (HGNC:12731): (WASP actin nucleation promoting factor) The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase, Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. Wiskott-Aldrich syndrome is a rare, inherited, X-linked, recessive disease characterized by immune dysregulation and microthrombocytopenia, and is caused by mutations in the WAS gene. The WAS gene product is a cytoplasmic protein, expressed exclusively in hematopoietic cells, which show signalling and cytoskeletal abnormalities in WAS patients. A transcript variant arising as a result of alternative promoter usage, and containing a different 5' UTR sequence, has been described, however, its full-length nature is not known. [provided by RefSeq, Jul 2008]

WAS Gene-Disease associations (from GenCC):

• Wiskott-Aldrich syndrome

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• X-linked severe congenital neutropenia

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• thrombocytopenia 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000232828 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-48684427-AC-A is Benign according to our data. Variant chrX-48684427-AC-A is described in ClinVar as Benign. ClinVar VariationId is 2934801.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376701.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAS	NM_000377.3	MANE Select	c.273+11delC		intron	N/A	NP_000368.1
	WAS	NM_001438877.1		c.273+11delC		intron	N/A	NP_001425806.1
	WAS	NM_001438878.1		c.273+11delC		intron	N/A	NP_001425807.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAS	ENST00000376701.5	TSL:1 MANE Select	c.273+5delC		splice_region intron	N/A	ENSP00000365891.4
	WAS	ENST00000698635.1		c.273+5delC		splice_region intron	N/A	ENSP00000513850.1
	WAS	ENST00000698626.1		c.273+5delC		splice_region intron	N/A	ENSP00000513845.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.00 AC: 0 AN: 161608 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000368 AC: 4 AN: 1085985 Hom.: 0 Cov.: 32 AF XY: 0.00000283 AC XY: 1 AN XY: 353869

African (AFR) AF: 0.00 AC: 0 AN: 25990

American (AMR) AF: 0.0000295 AC: 1 AN: 33941

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19155

East Asian (EAS) AF: 0.00 AC: 0 AN: 29257

South Asian (SAS) AF: 0.00 AC: 0 AN: 52487

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00000359 AC: 3 AN: 836054

Other (OTH) AF: 0.00 AC: 0 AN: 45591

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 51

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.054

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs58371799; hg19: chrX-48542816;